Prevalence and severity of disease varies geographically in the wide array of mammals and birds that protozoan pathogens infect. To reduce the burden of emerging parasitic disease among prevalent zoonoses, a primary goal of our work is to discover the transmission dynamics and the phylogenetic relationships among circulating protozoan parasites that possess complex life cycles and multiple routes of transmission in nature. We seek discoveries in these areas to support the development of new diagnostic tools, identify fundamental paradigms governing virulence shifts in parasitic protozoa and develop efficacious anti-protozoal strategies that mitigate the spread of disease. Periodic shifts in the population genetics and transmission dynamics of pathogenic clones of protozoal agents such as Toxoplasma gondii, Sarcocystis neurona, Leishmania spp., and Giardia spp., have been of substantial interest to the parasitology community because these heteroxenous pathogens possess surprisingly clonal population genetic structures that are punctuated by the dominance of only a few highly successful clones. The genetic basis for how these clones emerge and then rapidly come to dominate has been a matter of intensive study, and great debate. We previously showed that some protozoan parasites possess the distinct ability to functionally clone themselves via unisexual (or self-) mating during their sexual cycle in nature, so this exists as an important factor governing the expansion of emergent clones that can sweep to dominance, or cause virulent epidemics. These data served as the first extensive from-the-field evidence that self-mating is a key adaptation allowing expansion of parasite clones capable of causing disease epidemics. Metabolic potential is increasingly being viewed as another critical element governing a pathogens virulence potential, as well as its ability to survive in infected hosts. Through modulating metabolic capacity, parasites are able to tune their growth in response to changes in host environment, offering a potential route to expand their host range, ecological niche, or cause new disease. It is increasingly apparent that enteric parasites and fungi function as keystone species and specifically modulate the host microbial environment, which has important implications in the development, regulation and efficacy of immune function in the context of disease pathogenesis. Our recent work has used genome-level population genetic, metagenomic, metabolic reconstruction and molecular epidemiology to determine how a variety of pathogens replicate and cause disease across a broad range of intermediate hosts. We are producing genome level ancestry models for a variety of prevalent zoonoses to determine how genome-level structural variation, recombination, and admixture combine to confer strain-specific differences in growth and virulence potential. And specifically, how these genetic variants modulate host microbial interactions to impact host immune cell development and regulation. These datasets have identified new drug targets for therapeutic intervention.